The use of liposomes as a drug delivery system to enhance the efficacy and/or reduce the toxicity of antitumor agents seems extremely promising. However, present formulations of drug bearing liposomes are taken up mainly in liver and spleen by the phagocytic macrophages of the reticuloendothelial system (RES); this pattern of uptake limits opportunities for interactions between tumor cells and liposomes carrying antineoplastic drugs. This is quite important to develop approaches which will allow liposomes to evade RES uptake and achieve a longer lifetime in the circulation and a more favorable tissue distribution. At present surprisingly little is known of the interactions between liposomes and RES phagocytes either in vitro or in vivo; it is the intent of this proposal to study these interactions. Thus we will try to ascertain whether the mechanism of liposome uptake by macrophages in vitro is via endocytosis, fusion or by other processes. We will study the role of RES cells and of circulating factors (opsoning) in the clearance of liposomes in vivo and will seek to identify the opsonin(s) for liposomes if one exists. We will ivnestigate the behavior in vitro and in vivo of novel formulations of liposomes containing glycolipids or glycoproteins and having membranes stabilized against enzymatic or mechanical disruption. We will use information from these studies to develop liposome formulations with reduced RES uptake. We will load such liposomes with cytosine arabinoside and compare the pharmacokinetics and pharmacology of the drug given in this form to that of the free drug. In addition, we will make a preliminary study of the possibility of using liposomes as a vector to selectively deliver drugs to activated macrophages.